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S1PR3 modulates the hyper-proliferation of keratinocytes in psoriasis by activating STAT3 in PKA/Src dependent manner

ABSTRACT: Background: Abnormal lipid metabolism influences the occurrence and development of psoriasis. Moreover, persistent activation of STAT3 signaling pathway in epidemies contributes to psoriasis. However, the molecular mechanism of lipid metabolism and STAT3 activation is unclear. Methods: Imiquimod (IMQ)-induced mouse psoriasis-like model was established to access the potential treatment of FTY720. The function of SIP receptors 3 (S1PR3) was determined by S1PR3 siRNA in HaCaTs and S1pr3 knock out in mice. RNA-seq in HaCaTs was undertaken to explore the downstream target of S1PR3. ChIP assay was applied to explore the transcription factor on S1PR3 promoter. Findings: The upregulation of S1PR3 in the lesion from psoriasis patients and IMQ-induced mice was observed. Moreover, the pan-S1PR modulator FTY720 ameliorated the lesion in IMQ-induced mice, which was mediated by internalizing S1PR3. S1PR3 knocking downing both in vivo and in vitro significantly suppressed the hyper-proliferation of keratinocytes in a P-STAT3-dependent manner. We found that upregulated-S1PR3 expression maintained STAT3 activation in psoriasis through both short and long term. Namely, S1PR3 enhanced early STAT3 activation via promoting the binding of P-Src to gp130, and long STAT3 activation by reducing Src. Ultimately, Upregulated-S1PR3 was due to STAT3 binding to S1PR3 promoter in psoriatic skin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268738 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background: Imiquimod (IMQ) produces a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis. Whether this phenotype depends on strain or sex has never been systematically investigated on a large scale. Such effects, however, could lead to conflicts among studies, while further impacting study outcomes and efforts to translate research findings. Methods: RNA-seq was used to evaluate the psoriasiform phenotype elicited by IMQ in both sexes of 7 mouse strains (C57BL/6J, BALB/cJ, CD1, DBA/1J, FVB/NJ, 129X1/SvJ and MOLF/EiJ). Results: In most strains, IMQ altered gene expression in a manner consistent with human psoriasis, partly due to innate immune activation and decreased homeostatic gene expression. The IMQ response of MOLF males was aberrant, however, with decreased expression of differentiation-associated genes (elevated in other strains). Key aspects of the IMQ response differed between the two most commonly studied strains (BALB/c and C57BL/6). Compared with BALB/c, the C57BL/6 phenotype showed increased expression of genes associated with DNA replication, IL-17A activation and CD8+ T cells, but decreased expression of genes associated with interferon signaling and CD4+ T cells. Surprisingly, although IMQ-induced expression shifts mirrored psoriasis, correspondence was similar or better for other human skin diseases (e.g., eschars, acne, atopic dermatitis). For BALB/c, MOLF, and 129X1 strains, genes altered by IMQ corresponded better to those altered in human skin infections or wounds compared with those altered in psoriasis lesions. Conclusions: These findings demonstrate strain-dependent aspects of IMQ dermatitis that warrant consideration in planning and interpreting experimental studies. We have further shown that IMQ does not uniquely model psoriasis but in fact triggers a core set of pathways active in diverse skin diseases. These observations challenge the view of IMQ dermatitis as a mouse phenotype uniquely appropriate for studying psoriasis as opposed to other human skin conditions.

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S1PR3 modulates the hyper-proliferation of keratinocytes in psoriasis by activating STAT3 in PKA/Src dependent manner

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